Eatris.it

Ann Ist super sAnItà 2008 | Vol. 44, no. 1: 57-63
Francesca Baldi and Alberto MantovaniDipartimento di Sanità Pubblica Veterinaria e Sicurezza Alimentare, Istituto Superiore di Sanità, Rome, ItalySummary. Diet is a significant source of exposure to endocrine disrupting chemicals (EDC); health
risks cannot be excluded, in particular long-term effects in vulnerable groups such as children.
However, food safety assessment must also consider the effects of natural food components modu-
lating the endocrine system. The scientific evidence on the complex interactions between EDC and
food components is still limited. The new EDC-Diet Interactions Database (EDID) within the ISS
EDC area (www.iss.it/inte/) aims to stimulate further research in the field of food toxicology: a data-
base on international literature’s studies, either on experimental systems and on animal population
and humans, easy to consult and periodically updated. Examples of studies contained in EDID are
provided concerning EDC with iodine, vitamins and phytoestrogens.Key words: risk assessment, risk-to-benefit-analysis, toxicology, nutrition, endocrine disrupters, contaminants,
Riassunto(Una nuova base di dati sulla sicurezza alimentare: EDID (Endocrine disrupting chemicals - Diet Interaction Database). L’alimentazione è un’importante via di esposizione ad interferenti
endocrini (endocrine disrupting chemicals, EDC), con possibili effetti a lungo termine su gruppi
vulnerabili come l’infanzia. Tuttavia la valutazione del rischio in sicurezza alimentare deve anche
considerare gli effetti di componenti naturali degli alimenti con potenziali effetti endocrini. Le evi-
denze scientifiche per caratterizzare le complesse interazioni fra EDC e componenti alimentari sono
ancora limitate. Il nuovo database EDC-Diet Interactions Database (EDID) all’interno dell’area
tematica “interferenti endocrini” (www.iss.it/inte/) intende contribuire a sviluppare la ricerca nel-
la tossicologia alimentare. EDID comprende articoli internazionali, riguardanti sistemi sperimen-
tali, popolazioni animali e l’essere umano, di facile consultazione ed aggiornata periodicamente.
Vengono illustrati esempi di studi presenti in EDID riguardanti le interazioni di EDC con iodio,
vitamine e fitoestrogeni.Parole chiave: valutazione del rischio, analisi rischio-beneficio, tossicologia, alimentazione, interferenti endo-crini, contaminanti, fitoestrogeni.IntRoductIon
tive substances may modulate the endocrine system
Endocrine disrupting chemicals (EDC) are an het-
function, from trace elements such as iodine, which
erogeneous group of substances present in the diet
are also essential micronutrients [3] to the numerous
and environment able to modify endocrine home-
group of “phytoestrogens”. Phytoestrogens are sub-
ostasis, in particular steroid and thyroid hormones;
stances present in plants that may interact with es-
therefore reproductive health and developing life
trogen receptors; examples include genistein, an iso-
stages are the most susceptible targets [1]. EDC
flavone found in soy, as well as less well-known com-
interact with nuclear receptors or with enzymes
pounds present in different grains and fruits, such
responsible of synthesis or transportation of hor-
as daidzein, quercetin, resveratrol, lignans, etc. [4].
mones; they include persistent contaminants (e.g.,
EDC arouse concern because of their potential for
dioxins, polychlorinated biphenyls), compounds
both long-term, multiple-target effects on vulnerable
used in plant and/or animal production (e.g., dicar-
lifestages as well as for general population exposure
boxmides, triazoles) and compounds found in indus-
associated with the bioaccumulation capability, and/
trial as well as consumer products (e.g., bisphenol
or to widespread diffusion of different compounds
A, several phthalates, polybrominated flame retard-
[1, 2]. Indeed, EDC exposure in the early lifestages is
ants) [2]. Endocrine-active chemicals are not con-
strongly suspected for the reproductive health dete-
fined to xenobiotics. Indeed, many natural bioac-
rioration observed in many industrialized Countries
Address for correspondence: Alberto Mantovani, Dipartimento di Sanità PubblicaVeterinaria e Sicurezza Alimentare, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail: alberto.mantovani@iss.it.Francesca Baldi and Alberto Mantovani
[5]. Consequently EDC are one of the chemical con-
conception of food toxicology cannot consider diet
tamination problems that drew great attention by
just as an exposure source of external harmful sub-
the scientific community and public opinion. This
stances. Contaminants such as EDC may interact
is reflected, at European level, by the novel devel-
with the same metabolic pathways as natural food
opments of testing strategies, especially in the field
components such as polyunsaturated fatty acids,
of reproductive and developmental toxicology [6],
trace elements, vitamins and other bioactive sub-
as well as by the many research projects on EDC
stances (e.g. polyphenols) that cannot be consid-
[7]. A specific task force on testing and assessment
ered nutrients as there is no recognized deficiency.
of EDC has also been set up within the chemical
Dietary habits are related to socioeconomic status,
programme of the Organisation for Economic Co-
cultural and religious factors, individual choices
operation and Development (OECD) [8]. Due to the
(e.g. vegetarianism/veganism); in their turn dietary
high and up-to-date relevance of EDC research to
habits may have a most important impact on the
the fields of food and environmental safety as well
intake of either nutrients and contaminants. For in-
as of preventive medicine, the Istituto Superiore di
stance, the changing dietary habits in Italy lead to a
Sanità (ISS) has launched since 2002 a dedicated
lower intake of specific vitamins (folic acid, B6 and
website, that is updated weekly, with a full English
E) as compared to that expected in the traditional
version and a special interest to collect information
“Mediterranean diet” [15]; also, greater exposure
on ongoing Italian research as well as on emerging
to persistent EDC is associated with the high con-
sumption of fatty foods of animal origin [16]. Thus,
for specific food commodities a balanced evaluation
is needed about contaminant-associated risks and
EndocRInE dISRuptIng
nutritional benefits. The most up-to-date example is
chEMIcAlS, dIEt And nutRIEntS
represented by salmonids and other seafood, both
Diet is a particularly significant source of exposure
wild and farmed, that are a useful source of nu-
to EDC for the general population. The suspicious-
trients such as polyunsaturated fatty acids as well
ness of EDC assumption via diet is a source of con-
as a major source of exposure to EDC and other
cerns and “alarms” more or less justified for consum-
contaminants able to bioaccumulate such as meth-
ers’ health. One major issue is the “cocktail” effect.
ylmercury; therefore, evidence might justify recom-
Residue monitoring data in Europe indicate that
mendations to increase as well as to reduce fish con-
regulatory limits are exceeded in a minority of cases,
sumption, quite an uneasy situation for risk manag-
at least concerning compounds for which such limits
ers and public health policy makers [17]. Indeed, as
do exist, e.g. pesticides [9]; however, one cannot rule
response to several pollution “alarms” in northern
out altogether additivity of different EDC present in
Countries, the European Food Safety Authority
whole diet at low-level, but hitting the same targets,
(EFSA) issued in 2005 its first risk-to-benefit opin-
e.g. nuclear receptors [10]. Furthermore, it is not just
ion about consumption of wild and farmed fish
the daily dose that matters. Many EDC can bioac-
[18]. The EFSA document concluded that decreas-
cumulate, especially in body lipids, forming a “body
ing fish consumption (and its nutritional benefits) is
burden” of contaminants of different origin that can
not necessary in Europe; in the meanwhile, recom-
include dioxins, banned compounds that still persist
mendations included to continue the monitoring of
in the environment (polychlorinated biphenyls, chlo-
contaminants in edible fish as well as the support to
rinated pesticides and their metabolites), and bromi-
development of novel aquaculture feeds, less liable
nated flame retardants [11]. Other compounds, even
to contamination. Most important, effects of con-
though less persistent, may nonetheless concentrate
taminants and of natural food components are not
in food chains and/or body tissues, thus adding to
running in parallel; in most instances, they interact
the overall EDC internal burden; examples are
on the same pathways and targets. It can be inferred
phthalates [12] and organotins [13]. Thus, the po-
that a well-balanced diet, with a good intake of anti-
tential risk is less related to the contamination of a
oxidants, may be partly protective towards the ef-
single food commodity than to the long term intake
fects of toxic exposures. The interactions may not be
through the overall diet, whose impacts on the total
always so straightforward, however, as several nutri-
EDC body burden as well as on chronic health ef-
ents and bioactive components can exert adverse ef-
fects are incompletely known. Another issue to be
fects. An example are phytoestrogens, that can offer
considered in risk assessment is different vulnerabili-
a protective effect against some hormone-dependent
ties within the general population: concerning EDC,
cancers, as well as postmenopausal osteoporosis,
those best recognized are related to age and gender.
but may also interfere with receptor-mediated signal
For instance, children can be considered as a group
transduction (e.g. by inhibiting protein kinase) and
at higher risk, due to higher relative consumption of
DNA replication, which might also lead to promot-
food and water as compared to adults as well as to
ing the proliferation of some cancer cells [19]. One
the ongoing functional development of reproduc-
cannot even exclude that high phytoestrogen dosage
tive, nervous and immune systems [14].
may have additive effects associated with contami-
However, other factors that can modulate vulner-
nants that target the same receptors. Up to date,
ability deserve adequate consideration. The modern
scientific data available on interactions between xe-
nobiotics and “natural” substances in food are still
are not typical EDC, while investigations on dioxins
meagre, in spite of the relevance that such topic may
and PCB took course years before the widespread
have in the food safety and prevention fields.
diffusion of the EDC concept. A simple, general
keyword like “endocrine” matched with nutrient-
relevant keywords (“trace element”, “vitamin”, nu-
EdId: EndocRInE dISRuptIng chEMI-
trient” or more specific ones) can be more effective,
cAlS - dIEt IntERActIon dAtABASE
although it obviously lacks specificity and requires
The new EDC - Diet Interactions Database (EDID)
careful selection of the really EDID-relevant papers.
within the ISS EDC website (www.iss.it/inte/edid/cont.
Currently, updating has to be performed through a
php?id=110&lang=2&tipo=17), started in 2006, is
selection of matched keywords (e.g., “PCB AND
the first database dedicated to interactions between
vitamin”, “Pesticide” AND “phytoestrogen”, etc.),
EDC and nutrients; currently it contains more than
extracting the relevant papers and the “fishing” col-
300 items. For setting and updating the database the
lection of related papers. Although such approach
terms “EDC” and “diet” needed definition. EDC is
has been satisfactorily effective in the first launching
taken in its broad sense, as in the 1996 Weighbridge
phase of EDID, that will end 24 months after start,
definition adopted in Europe as a chemical that can
the elaboration of a more systematic approach to
induce adverse effects on the health of an organism
literature search will be implemented in the follow-
or of its progeny through endocrine mechanisms
(see the ISS EDC website homepage www.iss.it/
inte/?lang=2; whereas “diet” includes all nutrients,
either macro- (protein, glucose, etc.) or micronutri-
ExAMplES oF EdId topIcS
ents (vitamins, trace elements), as well as bioactive
The following paragraphs deal with some of the
compounds that can be naturally present in foods,
main topics that can be found in the EDID database.
besides any man-made addition. EDID aims to be a
contribution for stimulating further research in the
Iodine, thyroid function and EDC
field of xenobiotics-nutrients interactions. EDID is
Iodine is the main determinant of thyroid develop-
conceived primarily as a database on studies pub-
ment and function; some food commodities of ani-
lished on international peer-reviewed literature, ei-
mal origin, namely seafood and milk, are the main
ther on experimental systems in vitro/in vivo, animal
dietary sources, nevertheless subclinical iodine de-
populations (both wild and farmed) and humans.
ficiency in humans and farm animals is still a com-
However, some relevant reports available on the web
mon problem in many areas, including Europe [3].
and issued by national or international Agencies
Thyroid is also an emerging target for EDC; it may
are also included, such as the already quoted EFSA
be reasonable to hypothesize that a low iodine sta-
opinion on fish consumption [18]. EDID aims at be-
tus would enhance the susceptibility to thyrostatic
ing a user-friendly database; it utilizes DSpace which
xenobiotics. Yet, it is unfortunate that only a limited
is one of the first open source software platforms to
number of papers till now deal with the relationship
store, manage and distribute its collections in dig-
between iodine status and EDC effects. Somewhat
ital format (http://dspace.iss.it/dspace/). Different
unexpectedly phthalates, widespread plasticizers
search criteria may be set, namely: a) words present
that rise concern mainly because of their antian-
in the article’s title; b) keywords not present in the
drogenic effects, can modulate basal iodide uptake
article’s title, including s, nutrients, animal species,
mediated by the sodium/iodide symporter in thyroid
targets (tissues, organs, enzymes, receptors etc.);
follicular cells in vitro [20]. Interestingly, the effect
usually four such keywords are selected for each
was not a general effect of phthalates and was inde-
paper; c) the author’s name (the first three if more
pendent from cytotoxicity; dibutyl phthalate was the
than three authors are present); d) the article’s re-
most cytotoxic out of the six compounds tested but
lease year. Due to current copyright regulations,
it did not modulate iodide uptake. Phytoestrogens
most documents present in EDID are available only
may also deserve more investigation as a study show
as abstracts: however, the corresponding author’s
that many of them may interfere with iodination of
address and full journal reference enables to easily
thyroid hormones: some (e.g., naringenin, and quer-
recover the full paper, when needed.
cetin, which contain a resorcinol moiety) are direct
EDID is periodically updated. The current lack
and potent inhibitors of thyroid peroxidase, where-
of standard keywords or search tools for papers on
as others (myricetin, naringin) showed noncompeti-
toxicant-nutrient interactions makes it necessary
tive inhibition of tyrosine iodination with respect
to perform an expert-based, case-by-case “fishing”
to iodine ion and biochanin A acted as an alternate
search. For instance, the keywords “endocrine dis-
substrate for iodination [21]. Indeed, a Czech bio-
rupter”, “endocrine disruptor” or “endocrine dis-
monitoring study in children without over hypothy-
rupting chemical” do not catch many papers on di-
roidism showed a modest but significant adverse
oxins, polychlorinated biphenyls or phytoestrogens,
relationship of serum concentrations of genistein,
although such keywords do perform more effec-
with markers of thyroid function, while no signifi-
tively with chemicals like phthalates, bisphenol A or
cant association was found for another isoflavone,
pesticides; the reason might be that phytoestrogens
daidzein. However, since even small differences in
Francesca Baldi and Alberto Mantovani
phytoestrogen intake were related to thyroid func-
P450 (CYP) 1A1, that in its turn may enhance the
tion, this might have an impact in children popula-
toxic effects of TCDD. Several studies indicated that
tions where iodine intake is insufficient [22].
concurrent supplementation of vitamin A could in-
hibit CYP1A1 activity (measured as ethoxyresoru-
Oxidative stress, antioxidant vitamins and EDC
fin-O-deethylase [EROD] activity). In particular, in
Activation of nuclear receptors such as the es-
mice orally treated with TCDD the concurrent ad-
trogen receptor alpha is closely related to redox
ministration of vitamin A reduces liver damage and
status and oxidative stress pathways [23]. Indeed,
the specific markers of TCDD action, namely the
one of the major clusters within EDID includes
augmented EROD activities, CYP1A1 expression,
papers showing that antioxidants such as vitamins
and AhR mRNA expression [29]. These findings
C and E exert a protective role towards the effects
suggest a relationship between vitamin A depletion
of EDC such as phthalates and PCB. Two exam-
and TCDD effects at molecular levels, at least in
ples are given. Di-(2-ethylhexyl) phthalate (DEHP)
liver tissue; however, the role of retinoic acid as a
may be the most potent EDC among phthalates
target within the wide range of adverse dioxin-in-
and it is surely the most thoroughly investigated;
duced effects still needs clarification. Organotins do
the compound can interfere with steroid synthe-
not bind to steroid nuclear receptors, but may alter
sis pathways by interacting with the Pregnane-X
steroid biosynthesis [13]. Tributyltin chloride and
nuclear receptor [24]. DEHP can severely disrupt
triphenyltin hydroxide, bind specifically to the RXR
spermatogenesis in adult rodents; however such
in human choriocarcinoma cells; binding elicit tran-
effects are reversible upon discontinuation of the
scriptional activation of endocrine signalling, e.g.
treatment. Supplementation with vitamins C and
aromatase, but not the retinoic acid pathways [30].
E can protect the seminiferous epithelium from
Thus, more research on the interactions of EDC
DEHP effects; moreover, the supplementation with
acting through different mechanisms with retinoic
both vitamins after the treatment significantly ac-
celerated regeneration of the testis epithelium [25].
Non-dioxin like PCB can alter endocrine homeos-
Phytoestrogens and xenobiotics
tasis through several, mainly non-receptor medi-
Due to their pleomorphic biological effects, in-
ated, mechanisms. The PCB mixture Aroclor 1254
cluding some potentially adverse ones, phytoestro-
was tested on cultured chicken embryo hepatocytes
gens could be considered a sort of “natural EDC”
with and without vitamin E, vitamin C and vitamin
[4, 19]. Most attention has been concentrated on
A, alone and in combination. Aroclor 1254 caused
the soy phytoestrogen genistein, possibly the most
irreversible damage to cell membrane integrity and
potent phytoestrogen; however, the overall dietary
increased cellular lipid peroxidation, whilst reduc-
intake of phytoestrogens may be significant in
ing glutathione levels and superoxide dismutase
Europe, even though lower than in Eastern Asia
activities. The vitamins, either alone and in combi-
[31]. Therefore the interactions between phytoes-
nation (A+E and C+E, apparently not A+C) sig-
trogens and EDC could represent a major topic of
nificantly attenuated the toxic effects; the findings
interest, due to combined presence in diet and pos-
in this system also suggest that lipid peroxidation
sible sharing of biological targets. Yet, periodical
may be a key event in PCB toxicity [26]. Still most
EDID updating has led to include less than 20 pa-
studies on EDC and antioxidant vitamins show a
pers on such issue till now. As phytoestrogens may
protective effect, but only few attempts to elucidate
have beneficial effects on human health, they have
mechanisms. Also, it would be interesting to have
been also hypothesized to compete with estrogenic
more comprehensive data on the combined impact
EDC, thus exerting a protective action. Indeed,
on EDC effects of dietary antioxidants, in the pro-
flavonoids (daidzein, genistein, quercetin, and
portion and amount provided by the different di-
luteolin) can suppress the induction of the prolif-
eration-stimulating activity of estrogen-like acting
EDC (4-nonylphenol, bisphenol A, and the PCB 4-
EDC and vitamin A
dihydroxybiphenyl) in MCF-7 cells [32]. The effect
Retinoic acid is the internal form of vitamin A
of mixtures containing 17beta-estradiol, 17alpha-
interacting with the nuclear receptors RAR and
ethinylestradiol, genistein, and estrogenic EDC
RXR; all-trans-retinoic acid and 9-cis-retinoic acid
(the plastic additive bisphenol A, and the anionic
are the natural ligands for RAR and RXR, respec-
detergent by-products 4-nonylphenol, and 4-tert-
tively. In its turn, retinoic acid pathways cross-talk
octylphenol.) was less than additive when assessed
with that of the aryl hydrocarbon receptor (AhR),
through the proliferation of estrogen-dependent
the direct cell target for dioxins and dioxin-like
MCF-7 human breast cancer cells; the partly ana-
compounds [28]. Thus, it is relevant to investigate
tagonistic interaction was observed in particular
the specific interactions between EDC and vitamin
between the other compounds, including genistein,
A metabolism. However, up to now only a few have
and 4-nonylphenol and 4-tert-octylphenol [33].
been clearly shown to interfere with this pathway.
In some cases no interaction can be observed: the
The most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-
combined treatment with genistein did not modu-
p-dioxin (TCDD) is a potent inducer of cytochrome
late the in vitro effects on human astroglial cells
of two persistent EDC, the polybrominated flame
polyborominated flame retardants or organotins
retardant PBDE-99 and the PCB mixture Aroclor
are much less represented, even though their cur-
1254 [34]. The available findings in vivo provide a
rent exposure levels do create concerns for food and
more complex picture. Genistein and the estrogenic
environmental safety [11-13]. It is also somewhat
chlorinated insecticide methoxychlor were tested on
surprising that a number of papers on toxicant
rats alone or in combination, to assess possible ef-
(including EDC)-nutrient interactions were issued
fects on immune function, a potential critical target
some 10-20 years ago, i.e., before the start or the
for EDC that is still somewhat underscored by the
full development of interest and research on EDC.
available literature. A possible additive effect was
Such papers, even though valuable, obviously can-
seen in the parental generation on the reduction of
not provide the in-depth information that could be
relative spleen and thymus weight as well as, to a
supported by the novel research tools of molecu-
lesser extent, of weight gain. In the F1 generation
lar toxicology [27-33], and that is required by the
the combined effect of genistein (at dose levels low-
conceptual framework of EDC risk assessment.
er than those effective in the parental generation)
Nevertheless, apparently the topic did not draw too
and methoxychlor had a significant detrimental im-
much attention from risk assessment or research-
pact on the total number of thymocytes as well as
funding agencies; this situation may rapidly change,
on the different CD4-CD8 subclasses [35]. New in-
due to food safety becoming a cutting-edge topic for
sights are provided by a recent paper using estrogen
both research and public health as well as the new
reporter (ERE-tK-Luciferase) male mice. Genistein
developments of risk-to-benefit analysis. Indeed, as
can partially accumulate in body fat depots where it
other topics become “fashionable”, a new output
may persist for weeks at functionally active levels;
of papers is expected, e.g. on risk-to-benefit analy-
following fasting genistein is released from adipose
sis of contaminants and nutrients in seafood [17,
tissue in the circulation and can modulate the ac-
18]. Other shortcomings of the database reflect
tions of either estradiol and persistent EDC in liver
more wider knowledge gaps. For instance, the soy
and testis with tissue-specific features. In particular
isoflavone genistein is the only phytoestrogen that
genistein reversed the antiestrogenic action of beta-
is thoroughly investigated, even though other com-
benzene-hexachloride in the tesis and of o,p’-DDT
pounds, e.g. lignans, may have a higher intake from
in the liver, whereas it had an additive effect with
European populations [31]. Most important, there
the ER agonist p,p’-DDT in the liver [36]. Thus, the
are still a limited number of human epidemiologi-
available data can only indicate that interactions
cal studies that concurrently investigated mark-
between phytoestrogens and EDC can be important
ers of toxicant exposures and of nutrient intake.
but also that they cannot simply explained in terms
Examples include: the assessment of long-term per-
of additivity or antagonism; as a consequence the
chlorate exposure thorough drinking water, thyroid
dietary intake of phytoestrogens cannot be consid-
markers and iodine in urine and breast milk that
ered per se a protective factor towards exposures to
has been carried out in Northern Chile and found
environmental EDC. More research should be war-
no significant impact [37]; the intervention study
ranted on phytoestrogens other than genistein as
with folic acid, carried out on adults from an ar-
well as biomonitoring studies in humans on both
senic-polluted area of Bangladesh, indicating that
ohytostrogens and contaminants using appropriate
folic acid supplementation enhances arsenic meth-
ylation, hence metabolism and excretion, in sub-
jects with low plasma folate [38]. Therefore, a full
assessment of EDID content, development accessi-
concluSIonS
bility and usability will be performed after the first
EDID represents a novel instrument for research
in food toxicology, that will be implemented and in-
Yet, notwithstanding the unavoidable problems of
creased as the EDID issues will receive increasing
a starting phase, increasing evidence supports the
attention from research and risk assessment. The
hypothesis originating EDID, i.e., that diet is a sub-
shortcomings of EDID are these of the available
stantial risk modulator of EDC-related health risks
literature. As no systematic projects or actions do
and that an evidence-based assessment of the com-
exist yet on the interface between EDC and dietary
plex EDC-diet interactions is required [31, 33, 34].
components, it is unavoidable that the presence of
Thus, in perspective EDID may provide important
a given topic is related to the interest (and success)
information and tools also to preventive medicine,
of a given research group. Examples, as mentioned
namely i) nutritional markers that are relevant to
above, are the paucity of studies on iodine uptake
the susceptibility to specific EDC or EDC groups
modulation by EDC and the comparative abun-
[37] and ii) dietary interventions or supplementa-
dance of papers investigating the putative protec-
tion that may be performed with population groups
tive role of the antioxidant vitamins C and E. Also,
exposed to EDC that interfere with metabolism of
a large proportion of papers present in EDID deal
with “old” contaminants such as dioxins, PCB and
Finally, as pointed out by the EFSA [39], new ap-
to a lesser extent heavy metals; other, more recent
proaches are needed in food safety, encompassing
EDC such as phthalates, bisphenol A, nonylphenol,
also a comprehensive of the health impact – either
Francesca Baldi and Alberto Mantovani
detrimental and/or beneficial – of a given food com-
Acknowledgements
modity. When required, decision makers should be
EDID has been elaborated within the frame of the ISS special
provided with a balanced assessment of toxicologi-
Project “Interferenti Endocrini” (resp. A. Mantovani) as well as
cal and nutritional risks and benefits; thus the devel-
of the 6th FP Network of Excellence CASCADE (www.casca-
opment of a knowledge basis on toxicant-nutrient
interactions is most critical for a science-supported
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M5045 Lantus_CMEFacGde_Pad 9/27/06 1:40 PM Page 1**Tony_Weir **MacHD: Tony Weir-Jobs:Current Jobs: M5045 Lantus: Starting insulin: • It is important to monitor your blood sugars closely as you patient guide • Record your blood sugars every day before breakfast and2–3 other times every day; test before meals unless your• You and your doctor have decided that you will start • Reco